Gene therapy restores hearing and balance in mice

Nature Biotechnology

February 7, 2017

Efficient delivery of genes to the mouse inner ear and unprecedented correction of hearing loss and balance symptoms in a mouse model of a rare genetic hearing disorder are reported in two papers published online this week in Nature Biotechnology. If the viral delivery technology used in these studies can be translated to the clinic, it would represent a breakthrough in gene-transfer approaches to treat genetic diseases of the inner ear.

Genetic hearing disorders are estimated to affect 125 million people worldwide and have been linked to mutations in more than 100 genes. A large body of research has shown that various genetic diseases can be cured in animals and humans using benign viruses engineered to carry normal copies of genes into different organs. Until now, however, scientists have not succeeded in identifying a virus capable of efficiently entering the cells of the inner ear (cochlea), particularly a subset of cells known as ‘outer hair cells’, which tune the responses of ‘inner hair cells’ to sound waves. In many cases of genetic hearing loss, delivery of genes to both outer and inner hair cells is needed to confer normal hearing ability.

In the first paper, Konstantina Stankovic, Jeffrey Holt, Luk Vandenberghe, and colleagues show that a synthetic variant of adeno-associated virus - a small virus that infects humans without causing disease - efficiently delivers a gene encoding a fluorescent protein to mouse outer and inner hair cells. Safety studies found that the procedure, including injection through the round window membrane, had no adverse effects.

In the second paper, Gwenaelle Geleoc and colleagues use the same viral vector to treat mice carrying a mutated gene responsible for Usher syndrome type IC, a childhood genetic disease that causes deafness, balance dysfunction, and blindness. Delivery of a normal copy of the mutated gene, Ush1c, to the cochlea soon after the mice were born led to high levels of Ush1c protein in outer and inner hair cells, repair of damaged hair cell bundles, and a robust improvement in hearing and balance behaviour, enabling profoundly deaf mice to hear sounds at the level of whispers.